It is estimated that over 8 percent of the world population is affected with diabetes mellitus, including about 26 million people in the United States alone. Diabetes mellitus increases the risk of problems related to the body's vascular system. Macrovascular complications can lead to accelerated atherosclerosis, coronary heart disease, and peripheral arterial disease. In addition, microvascular complications can lead to retinopathy, nephropathy, and neuropathy. Studies show that diabetes mellitus increases the risk of the occurrence of cardiovascular disease, and about 68 percent of the people affected with diabetes mellitus die due to cardiovascular disease. Health care costs associated with cardiovascular diseases total close to $15 billion dollars. Because of the high prevalence of cardiovascular disease in patients with diabetes mellitus, this particular patient population must undergo a greater number of cardiovascular surgeries to repair or replace key components of the cardiovascular system, such as heart valves and blood vessels. These surgeries often result in more complications for diabetic patients than other patient populations.
One of the complications associated with cardiovascular repair or replacement surgeries in patients with diabetes mellitus is that in diabetic environments, hyperglycemic conditions can result in the irreversible oxidation of lipids, proteins, and nucleic acids, which results in the formation of advanced glycation end products (AGEs). The formation of AGEs often results in endothelial dysfunction, accelerated atherosclerosis, inflammation, and calcification. Other complications are associated with inadequate biomechanical function of the aortic valve due to valvular stenosis and calcification.
In addition to AGE formation, glycoxidation in a diabetic environment is also directly influenced by oxidative stress. This oxidative stress can be induced by the formation of reactive oxygen species (ROS), which are free radicals. While not fully understood, it is believed that ROS formation is likely due to a combination of alterations of intracellular proteins, particularly in the mitochondria, and inflammatory cell (i.e., neutrophils and macrophages) recruitment. Many AGE formations, discussed above, depend on the presence of ROS, and further ROS may be produced by AGE formation.
Still other complications related to diabetes mellitus include an adverse effect on wound healing and matrix remodeling, which are integral aspects of matrix scaffold-based tissue engineering, which is being used to treat pathological complications due to cardiovascular disease. Tissue engineered scaffolds have been derived from xenogenic extracellular matrix (ECM) because of its ideal natural, three-dimensional architecture and its ability to remodel and become quickly and completely degraded. However, ECM scaffolds that are implanted into diabetic patients do not behave the same as those implanted into non-diabetic patients, and the ECM scaffolds often show increased stiffness and inflammation, which can be attributed to the formation of AGEs in a hyperglycemic and oxidative environment, resulting in irreversible crosslinking, impaired remodeling and regeneration, and fibrosis.
As such, there is a need for an improved cardiovascular implant that can be used in patients with diabetes mellitus that is not as susceptible to the damaging effects of AGEs. In particular, treating implantable devices or scaffolds with a phenolic compound could provide a means of mitigating diabetes-related complications associated with implantable devices due to a hyperglycemic environment and glycoxidation. Phenolic compounds are a diverse group of materials that have been recognized for use in a wide variety of applications. For instance, they naturally occur in many plants, and are often a component of the human diet. Phenolic compounds have been examined in depth for their efficacy as free radical scavengers and neutralizers, for instance in topical skin applications and in food supplements. Phenolic compounds are also believed to prevent the cross-linking of cell membranes found in certain inflammatory conditions and are believed to affect the expressions of specific genes due to their modulation of free radicals and other oxidative species.